Here we seek to clarify the molecular mechanisms by which a transcription factor called HHEX restricts the ability of neurons to extend axons, and explore the potential of interfering with HHEX function to promote axon growth in the central nervous system. This work is significant because the low regenerative ability of neurons in the central nervous system prevents full recovery from stroke, neurodegenerative disease, or injury to the brain or spinal cord. A major therapeutic goal is to enhance regenerative ability in CNS neurons, but the molecular mechanisms that restrict growth remain incompletely understood. HHEX, which has been linked to cellular growth in cells outside the nervous system but is largely unstudied in the brain, emerged unexpectedly from a large-scale screening experiment that examined the effect of various transcription factors on the morphology of cortical neurons. Expression of HHEX strongly decreases axon growth. Furthermore, HHEX is expressed in adult CNS neurons that regenerate poorly, but not in regeneration-competent neurons in the peripheral nervous system. Finally, a structure-function analysis revealed that HHEX blocks axon growth by suppressing target genes, and that an artificial construct that activates HHEX target genes reverses the normal activity, that is, enhances axon growth. Combined, these data suggest that HHEX acts as a novel factor that suppresses axon growth ability in CNS neurons, and that manipulating HHEX function can promote axon growth. In this grant we will 1) clarify the set of genes that are regulated by HHEX in order to clarify the mechanism of growth suppression and 2) test the ability of HHEX-based manipulations to promote axonal sprouting and regeneration in an animal model of spinal cord injury. Ultimately, these studies will fill a critical gap in knowledge in the field through the identification of novel transcriptional components that regulate CNS regeneration, and explore the potential of this new target to improve regenerative capacity.